Summary: Francisella tularensis, the causative agent for tularemia, can infect humans by a number of routes, including vector-borne transmission. However, it is inhalation of the bacterium, and the resulting pneumonic tularemia, that represents the most dangerous form of disease. This is due to the short incubation time (3-5 days), non-specific symptoms, and a high mortality rate (greater than 80%) in untreated individuals. Furthermore, F. tularensis has been weaponized by both the United States and the former Soviet Union making it a viable candidate for use as a biological weapon. Despite over 80 years of research on F. tularensis around the world, very little is understood about the dynamic interaction of this bacterium with the host, especially following aerosol infection. My laboratory recently shown that, similarly to murine cells, human dendritic cells are acutely susceptible to infection with F. tularensis, but fail to produce pro-inflammatory cytokines or undergo maturation. Further, virulent F. tularensis actively interferes with the ability of human DC to respond to secondary stimuli. One explanation for the poor responsiveness of human DC following infection with F. tularensis is that these cells lack CD14. CD14 appears to be a critical player in the elicitation of inflammation following exposure of cells to F. tularensis. Cells that lack CD14 are still susceptible to infection, but fail to produce pro-inflammatory cytokines. Furthermore, these cells become refractory to further stimulation by other microbial components. The specific role and the mechanism in which F. tularensis and its components interacts with CD14 is currently under investigation in the laboratory. F. tularensis negatively regulates human dendritic cells through multiple pathways. For example, if the replication of extracellular bacteria is restricted, the ability of human dendritic cells to produce TNF-alpha in response to other microbial stimuli is restored. However, a similar restoration of IL-12 production is not observed. We are currently dissecting the specific pathways and molecular mechanisms by which virulent F. tularensis modulates host responses in human dendritic cells. In addition to aiding in the development of novel vaccines and therapeutics, identification of bacterial products capable of negatively regulating specific host pathways (while leaving others intact) may provide new targets for therapeutics directed against cancer and autoimmune diseases.